This is a prospective, real-world, patient-reported lifestyle study. Adults with CMT use a smartphone app, CMT&Me (Vitaccess Ltd; Oxford, UK), to enter regular data about CMT, its management, and its impact on their lives, over a period of at least two years.
Participation is entirely via the CMT&Me app. There are no physical study sites. Data is collected from participants in the following countries: France, Germany, Italy, Spain, the UK, and the USA.
Inclusion criteria are as follows:
- adult (age >18 years) diagnosed with CMT (self-reported diagnosis only)
- resident in one of the study countries
- willing to use their own smartphone/tablet
- willing to provide informed consent
There are no specific exclusion criteria.
Participants enrol and provide informed consent via the CMT&Me app. Participant briefing materials are presented in a series of pages on the app, each followed by an informed consent statement relating to that section. Participants who agree to all the statements are considered to have given informed consent. Consent includes agreement to the possibility of data being cross-referenced with other medical databases.
As this is a non-interventional study, participants are not expected to be at risk of physical harm. Participation may trigger negative feelings in some participants. Participants are able to contact the research team if they have concerns or questions and are advised to contact their medical team where necessary.
As the aim of the study is to provide a detailed view of the impact of CMT on patients in the real-world setting, we are aiming to collect as much data as possible. Outcomes are as follows:
- Date of birth
- Height and weight (to determine body mass index)
- Home postal code
- Healthcare system identifier (e.g., National Health Service number) [outcome only collected in countries where permitted]
- Smoking status (“Do you smoke?”, plus follow-up question to those answering yes to quantify often the participant smokes)Exercise status (“How often do you take this type of exercise [at least 20 minutes]?”)
- Diet status (the participant’s regular diet from a list of categories)
- Alcohol consumption status (how many units the participant drinks per day, factoring in differences in unit worth across countries)
- CMT subtype
CMT diagnosis and treatment
- Age at symptom onset
- Age when medical care was first sought
- Age at diagnosis
- Diagnostic tests performed to achieve CMT diagnosis
- Clinical examinations performed to understand CMT diagnosis
- Physical therapies received for CMT
- Medicines received for CMT
- Walking aids/orthotics received for CMT
- Type of medical professionals seen for CMT
- Frequency of visits to the emergency department
- Symptoms experienced
- Brief Fatigue Inventory (BFI)
- Patient-Reported Outcomes Measurement Information System (PROMIS™) Pain Intensity 3a
- PROMIS™ Pain Interference 6b
- Cramp frequency
- Cramp intensity
- Work Limitations Questionnaire (WLQ)
- Work/study status
- Days of work missed due to CMT
Health-related quality of life (HRQoL)
- EuroQol 5 Dimensions 5 Levels (EQ–5D–5L)
- PROMIS™ Sleep Disturbance 8a
- Falls Efficacy Scale—International (FES-I)
- Lower Extremity Function Scale (LEFS)
- Quick Disabilities of Arm, Shoulder & Hand (QuickDASH)
Planned sample size
We aim to enrol approximately 2,000 participants. A formal sample size calculation has not been performed as hypothesis testing is not planned and analysis is descriptive in nature.
Recruitment is community based, with potential participants made aware of the study via direct communication from CMT patient advocacy groups (PAGs), PAG and Vitaccess Ltd (CMT&Me app developer and study contract research organization) social media accounts, and word of mouth, including via PAG community networks and patient ambassadors.
Would-be participants are able to download the CMT&Me app from Apple’s App Store or Google Play, but study registration is contingent on meeting eligibility criteria.
The app was launched sequentially across the study countries in the following stages:
- Stage 1
- US English (15 October 2018)
- UK English (9 November 2018)
- Stage 2
- Germany (31 January 2019)
- Italy (31 January 2019)
- Stage 3
- Spain (8 April 2019)
- US Spanish (8 May 2019)
- Stage 4
Data collection and management
Participants are asked to complete a profile shortly after enrolment, which includes data on demographics, lifestyle characteristics, diagnosis and treatments, many of which are expected to remain fairly stable over the duration of the study. For those data that may change over the duration of the study (e.g., treatments, healthcare visits), participants are able—and encouraged—to add, edit or remove them.
Participants are also asked to complete a number of PRO instruments—after enrolment and then either monthly (EQ–5D–5L, BFI, PROMIS™ Pain Intensity 3a and Interference 6b, bespoke questionnaires for the study, PROMIS™ Sleep Disturbance 8a) or quarterly (WLQ, FES-I, LEFS, QuickDASH)—that assess HRQoL, specific symptoms, and function for up to two years. Summary descriptions of all PRO instruments are provided below.
The EQ–5D–5L comprises two parts: the EQ–5D–5L descriptive system and the EQ Visual Analogue Scale (EQ-VAS) .
The descriptive system comprises five dimensions (mobility, self-care, usual activities, pain/discomfort, and anxiety/depression), each with five levels (no problems, slight problems, moderate problems, severe problems, and extreme problems—i.e., higher scores represent worse health). The scores for the five dimensions are combined in a five-digit number describing the participant’s health state.
The EQ-VAS records the participant’s self-rated health on a vertical, visual analogue scale with endpoints labelled “the best health you can imagine” and “the worst health you can imagine”. Higher scores represent better self-perceived health.
The BFI assesses participants’ fatigue severity . The measure uses a 10-point numeric rating scale, and a recall period of 24 hours. A global fatigue score is calculated by averaging all nine items.
PROMIS™ Pain Intensity 3a and Interference 6b
The PROMIS™ Pain Intensity 3a includes two items that assess pain intensity over the last seven days (average and worst pain), and one for pain intensity “right now”; each scores using a five-point scale . Possible scores range from 2 to 10 where higher scores represent worst pain. This measure is generic rather than disease-specific.
The PROMIS™ Pain Interference 6b assesses the extent to which pain hinders engagement with social, cognitive, physical and recreational activities as well as enjoyment in life over the last seven days using a five-point scale . Possible scores range from 6 to 30 where higher scores represent greater interference. This measure is generic rather than disease-specific.
Bespoke questionnaires for this study
Two cramp-specific items were developed for inclusion in the study, measuring cramp frequency and intensity. The cramp frequency item asks, “In the past 7 days, how many days did you experience cramp?” and has five possible response options: had no cramp, 1–2 days, 3–4 days, 5–6 days, every day. The cramp intensity item asks, “In the past 7 days, how intense was your cramp at its worst?” and has five possible response options: had no cramp, mild, moderate, severe, very severe. Higher scores on both items represent greater cramp frequency and intensity respectively.
The WLQ measures the impact of CMT on participants’ work ability and productivity across four domains: time management, physical demands, mental-interpersonal demands, and output demands . Possible domain scores range from 0 to 100 and the recall period is the previous two weeks. WLQ domain scores will be converted into an estimate of productivity loss using an algorithm.
PROMIS™ Sleep Disturbance 8a
The PROMIS™ Sleep Disturbance 8a assesses self-reported perceptions of sleep quality, sleep depth, and restoration associated with sleep over the last seven days using a five-point scale . Possible scores range from 8 to 40 where higher scores represent worse sleep disturbance. This measure is generic rather than disease-specific.
The FES-I measures the level of concern about falling during social and physical activities inside and outside the home, whether or not the person actually carries out the activity . The “usual” level of concern is measured on a four-point Likert scale (1 = not at all concerned to 4 = very concerned), with participants asked to consider how they usually carry out the activity. Possible scores range from 16 to 64 where higher scores represent greater concern about falling.
The LEFS evaluates difficulties because of lower limb problems in 20 activities, including work/school activities, hobbies, moving around the home, dressing, lifting, standing, sitting, walking, and running . The level of difficulty is assessed for “today” using a five-point Likert scale (0 = extreme difficulty or unable to perform activity; 5 = no difficulty). Lower scores represent greater difficulties experienced because of lower limb problems.
The QuickDASH measure uses 11 items to gauge physical function and symptoms in people with any or multiple musculoskeletal disorders of the upper limb . All questions are rated 1 to 5 (no difficulty/none/not at all through to unable/extreme difficulty). Possible scores range from 11 to 55 where higher scores represent greater difficulties with physical function and symptoms.
Plans to promote participant retention and complete follow-up
If, at any study time point, participants do not complete data entry for a certain section of their profile or a PRO instrument within a one-week window, their data will be considered missing for that time point. They will still be able to enter data again at later required time points.
To promote engagement with the study app and continued data entry, participants will receive in-app messages, encouraging them to complete required data entry, thanking them for doing so, and stressing the importance of their contributions to research. Participants will also receive information about the study, updates on its progression, and emerging results via the study app, social media, and regular email newsletters.
CMT&Me also contains non-study features that are designed to help participants learn about or track their condition. These include a symptom tracker (which allows participants to record the severity of different symptoms at any given time and create a PDF diary that can be downloaded for personal use) and knowledge articles (multi-media information on the disease and treatments, based on validated information provided by PAGs). The collection of biometric data (e.g., heart rate, steps taken) via the study app and/or linkage to other apps/devices has also been explored, and is feasible, however nothing has been implemented at present. If it appears that these data would be valuable, collection of these data will be implemented subject to ethical approvals.
To promote data quality, rules were set for question responses (e.g., range limits for continuous variables, minimization of free-text data fields, limits to number of response options that can be selected). Data will also be checked and cleaned before analysis. Limits for continuous variables were determined in order to constrain erroneous data but still allow sufficient variation (e.g., height of eight feet would be prevented, but seven feet would be permitted). The minimization of free-text fields was to try to systematize responses to keep completion of the surveys relatively fast for participants; the same was true for limiting response options where possible. These were part of the registry’s testing and confirmed/refined as part of that process.
Each participant will log in to CMT&Me using unique self-generated login credentials, which are unknown and inaccessible to the study team. Data saved by participants in CMT&Me will be transferred to a central database, then aggregated and de-identified, as soon as is practicable. No personal data will be held on participants’ devices. Personally identifiable information (PII) will be encrypted with unique encryption keys at rest and all data will be encrypted in transit. All study data will be stored on a secure server.
All PII will be protected by industry-standard methods, ensuring full confidentiality is maintained. PII is not held on participants’ devices and cannot be viewed by the study sponsor or any external researchers who apply for access to the study data. Data will be stored in a central database in aggregated, de-identified form.
Statistical methods for primary and secondary outcomes
Data management and analysis will follow a pre-defined statistical analysis plan (SAP). As this is an exploratory observational study, differences and patterns in the data will be analyzed, but without exploring causation. All analyses will be descriptive, and no hypotheses tested.
Aggregated de-identified data will be summarized as follows:
- For continuous variables, distributions: number, mean, standard deviation, median, minimum, maximum, 95% confidence interval
- For categorical variables, summaries: n, frequency and proportion
For both variable types, the number and proportion of missing data will also be reported.
Descriptive distribution statistics for each PRO instrument score, or domain score, will be presented for baseline (first data entry timepoint) and at each time point thereafter, including at study end. Distribution statistics will also be generated to describe the outcomes at each time point for the absolute value and the calculated change from baseline.
Interim analyses will be conducted upon registration of the 1,000th participant and at 12-monthly intervals from study launch. The aim of the interim analyses is to inform the progression of key study outcomes, whether changes need to be made to existing survey structure, and whether further exploratory analyses outside of what is detailed in the SAP will be conducted.
A final analysis will be presented at study end (currently two years from study launch), based on data from all participants who have completed at least one PRO instrument, the necessary elements of their profile, and have been enrolled in the study.
Methods in analysis to handle protocol non-adherence and any statistical methods to handle missing data
Missing data will be handled as set out in the scoring guidelines for the PRO instruments, and according to best practice for the profile. All missing data will be assumed to be missing at random, and no adjustments will be made to account for missing data.
Plans to give access to the full protocol, participant-level data and statistical code
Members of the public and external researchers can apply via the study website to be granted access to aggregated and anonymized study data. Access decisions will be granted under the purview of the study scientific advisory board (SAB).
Oversight and monitoring
A key tenet of governance and monitoring is that the framework is transparent and public, and so accessible to would-be participants considering enrolling, as well as to enrolled participants. As such, all oversight and monitoring arrangements will be published on publicly available study webpages: https://vitaccess.com/cmt-and-me.
Composition of the data monitoring committee, its role and reporting structure
An SAB was convened during the study design phase to protect participants’ interest. The SAB is responsible for the following:
- Effective operational management of the study
- Ensuring that the study operates in the best interests of participants
- Ensuring that the study operates to the highest levels of academic rigor
The SAB acts as an advisory/review body for the following:
- Publication strategy and publications
- Data analyses
- Study evolution: possible amendments to the study protocol
- Communication: input into materials and communication with the participant cohort and wider CMT community.
The SAB also acts as a decision-making body for third party data access requests.
In line with good practice recommendations , the SAB comprises independent clinical and PAG representatives from each study country, plus sponsor and Vitaccess representatives. The SAB will meet in person at least annually (where feasible), and by teleconference at least every six months.
Adverse event reporting and harms
There is no obligation to report adverse events recorded by participants. Participants who report receiving the sponsor’s product PXT3003 (or other experimental drugs) would have already been enrolled in clinical trials, and it is assumed they would therefore be followed up under the relevant adverse event-reporting pathways.
Frequency and plans for auditing study conduct
The SAB will audit the study conduct on an ongoing basis.
Plans for communicating important protocol amendments to relevant parties
The study team will be responsible for communicating protocol amendments to relevant parties as necessary and must be approved by the SAB.
The sponsor and study team have developed a publications plan for the study, which was approved by the SAB, to include conference presentations and journal publications. Study progress and results will be communicated to participants on an ongoing basis through regular email, social media, and in-app communication (newsletters and data nuggets).